tbuckley/cabot-search huggingface dataset:
Effects of Medications on Heat Loss Capacity in Chronic Disease Patients: Health Implications Amidst Global Warming
Authors: Jericho Wee, Xiang Ren Tan, Samuel H. Gunther, Mohammed Ihsan, Melvin Khee Shing Leow, Doreen Su-Yin Tan, Johan G. Eriksson, Jason Kai Wei Lee
Journal: Pharmacological Reviews (2023)

Pharmacological agents used to treat or manage diseases can modify the level of heat strain experienced by chronically ill and elderly patients via different mechanistic pathways. Human thermoregulation is a crucial homeostatic process that maintains body temperature within a narrow range during heat stress through dry (i.e., increasing skin blood flow) and evaporative (i.e., sweating) heat loss, as well as active inhibition of thermogenesis, which is crucial to avoid overheating. Medications can independently and synergistically interact with ageing and chronic disease to alter homeostatic responses to rising body temperature during heat stress. This review focuses on the physiological changes, with specific emphasis on thermolytic processes, associated with medication use during heat stress. The review begins by providing readers with a background of the global chronic disease burden. Human thermoregulation and ageing effects are then summarised to give an understanding of the unique physiological changes faced by older adults. The effects of common chronic diseases on temperature regulation are outlined in the main sections. Physiological impacts of common medications used to treat these diseases are reviewed in detail, with emphasis on the mechanisms by which these medications alter thermolysis during heat stress. The review concludes by providing perspectives on the need to understand the effects of medication use in hot environments, as well as a summary table of all clinical considerations and research needs of the medications included in this review. <b>Significance Statement</b> Long-term medications modulate thermoregulatory function, resulting in excess physiological strain and predisposing patients to adverse health outcomes during prolonged exposures to extreme heat during rest and physical work (e.g., exercise). Understanding the medication-specific mechanisms of altered thermoregulation has importance to both clinical and research fraternities, paving the way for work towards refining current medication prescription recommendations and formulating mitigation strategies for adverse drug effects in the heat in chronically ill patients.
Functional Genetic Variants in <i>TGFβ1</i> and <i>TGFβR1</i> in miRNA-Binding Sites Predict Outcomes in Patients with HPV-positive Oropharyngeal Squamous Cell Carcinoma
Authors: Zihao Niu, Peng Sun, Hongliang Liu, Peng Wei, Jia Wu, Zhigang Huang, Neil D. Gross, Sanjay Shete, Qingyi Wei, Mark E. Zafereo, George A. Calin, Guojun Li
Journal: Clinical Cancer Research (2023)

TGFβ1 and TGFβ receptor 1 (TGFβR1) participate in regulation of the host's immune system and inflammatory responses and may serve as prognostic biomarkers for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC).This study included 1,013 patients with incident OPSCC, of whom 489 had tumor HPV16 status determined. All patients were genotyped for two functional polymorphisms: TGFβ1 rs1800470 and TGFβR1 rs334348. Univariate and multivariate Cox regression models were performed to evaluate associations between the polymorphisms and overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS).Patients with TGFβ1 rs1800470 CT or CC genotype had 70%-80% reduced risks of OS, DSS, and DFS compared with patients with TT genotype, and patients with TGFβR1 rs334348 GA or GG genotype had 30%-40% reduced risk of OS, DSS, and DFS compared with patients with AA genotype. Furthermore, among patients with HPV-positive (HPV+) OPSCC, the same patterns were observed but the risk reductions were greater: up to 80%-90% for TGFβ1 rs1800470 CT or CC genotype and 70%-85% for TGFβR1 rs334348 GA or GG genotype. The risk reductions were still greater (up to 17 to 25 times reduced) for patients with both TGFβ1 rs1800470 CT or CC genotype and TGFβR1 rs334348 GA or GG genotype compared with patients with both TGFβ1 rs1800470 TT genotype and TGFβR1 rs334348 AA genotype among patients with HPV+ OPSCC.Our findings indicate that TGFβ1 rs1800470 and TGFβR1 rs334348 may individually or jointly modify risks of death and recurrence in patients with OPSCC, particularly those with HPV+ OPSCC undergoing definitive radiotherapy, and may serve as prognostic biomarkers, which could lead to better personalized treatment and improved prognosis.
Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients
Authors: K. Ina Ly, Leland G. Richardson, Mofei Liu, Alona Muzikansky, Jonathan Cardona, Kevin Lou, Andrew L. Beers, Ken Chang, James M. Brown, Xiaoyue Ma, David A. Reardon, Isabel C. Arrillaga-Romany, Deborah A. Forst, Justin T. Jordan, Eudocia Q. Lee, Jorg Dietrich, Lakshmi Nayak, Patrick Y. Wen, Ugonma Chukwueke, Anita Giobbie-Hurder, Bryan D. Choi, Tracy T. Batchelor, Jayashree Kalpathy-Cramer, William T. Curry, Elizabeth R. Gerstner
Journal: Clinical Cancer Research (2023)

We evaluated the efficacy of bavituximab-a mAb with anti-angiogenic and immunomodulatory properties-in newly diagnosed patients with glioblastoma (GBM) who also received radiotherapy and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916).Thirty-three adults with IDH--wild-type GBM received 6 weeks of concurrent chemoradiotherapy, followed by 6 cycles of temozolomide (C1-C6). Bavituximab was given weekly, starting week 1 of chemoradiotherapy, for at least 18 weeks. The primary endpoint was proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥72%. Relative cerebral blood flow (rCBF) and vascular permeability (Ktrans) were calculated from perfusion MRIs. Peripheral blood mononuclear cells and tumor tissue were analyzed pre-treatment and at disease progression using RNA transcriptomics and multispectral immunofluorescence for myeloid-derived suppressor cells (MDSC) and macrophages.The study met its primary endpoint with an OS-12 of 73% (95% confidence interval, 59%-90%). Decreased pre-C1 rCBF (HR, 4.63; P = 0.029) and increased pre-C1 Ktrans were associated with improved overall survival (HR, 0.09; P = 0.005). Pre-treatment overexpression of myeloid-related genes in tumor tissue was associated with longer survival. Post-treatment tumor specimens contained fewer immunosuppressive MDSCs (P = 0.01).Bavituximab has activity in newly diagnosed GBM and resulted in on-target depletion of intratumoral immunosuppressive MDSCs. Elevated pre-treatment expression of myeloid-related transcripts in GBM may predict response to bavituximab.
When I use a word . . . . The spectrum of medical slang
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

The term "slang" is situated in the middle of a spectrum of linguistic items ranging from technical terms and jargon at one end to colloquialisms and cant at the other. Although the terms can be regarded as forming a continuum, there is much overlap between each and its neighbour and there is no easy definition of "slang" or classification of all the related terms. There are, however, many medical examples of all of them.
<scp>METTL14‐Mediated m6A</scp> Modification of <scp>TNFAIP3</scp> Involved in Inflammation in Patients With Active Rheumatoid Arthritis
Authors: Jifeng Tang, Ziqing Yu, Jinfang Xia, Renquan Jiang, Shuhui Chen, Detai Ye, Huiming Sheng, Jinpiao Lin
Journal: Arthritis & Rheumatology (2023)

The aim of the study was to investigate the role of N6 -methyladenosine (m6A) modification in the progression of rheumatoid arthritis (RA).Peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy controls were collected. The expression of m6A modification-related proteins and m6A levels were detected using polymerase chain reaction (PCR), western blot, and m6A enzyme-linked immunosorbent assay (ELISA). The roles of methyltransferase-like 14 (METTL14) in the regulation of inflammation in RA was explored using methylated RNA immunoprecipitation (MeRIP) sequencing and RNA immunoprecipitation assays. Collagen antibody-induced arthritis (CAIA) mice were used as an in vivo model to study the role of METTL14 in the inflammation progression of RA.We found that m6A writer METTL14 and m6A levels were decreased in PBMCs of patients with active RA and correlated negatively with the disease activity score using 28 joint counts (DAS28). Knockdown of METTL14 downregulated m6A and promoted the secretion of inflammatory cytokines interleukin 6 (IL-6) and IL-17 in PBMCs of patients with RA. Consistently, METTL14 knockdown promoted joint inflammation accompanied by upregulation of IL-6 and IL-17 in CAIA mice. MeRIP sequencing and functional studies confirmed that tumor necrosis factor α induced protein 3 (TNFAIP3), a key suppressor of the nuclear factor-κB inflammatory pathway, was involved in m6A-regulated PBMCs. Mechanistic investigations revealed that m6A affected TNFAIP3 expression by regulation of messenger RNA stability and translocation in TNFAIP3 protein coding sequence.Our study highlights the critical roles of m6A on regulation of inflammation in RA progression. Treatment strategies targeting m6A modification may represent a new option for management of RA.
Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With <i>KRAS<sup>G12C</sup></i>-Mutated Non–Small-Cell Lung Cancer Who Have Untreated CNS Metastases
Authors: Marcelo V. Negrao, Alexander I. Spira, Rebecca S. Heist, Pasi A. Jänne, Jose M. Pacheco, Jared Weiss, Shirish M. Gadgeel, Karen Velastegui, Wenjing Yang, Hirak Der-Torossian, James G. Christensen, Joshua K. Sabari
Journal: Journal of Clinical Oncology (2023)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Patients with Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated non-small-cell lung cancer (NSCLC) and untreated CNS metastases have a worse prognosis than similar patients without KRAS mutations. Adagrasib has previously demonstrated CNS penetration preclinically and cerebral spinal fluid penetration clinically. We evaluated adagrasib in patients with KRASG12C-mutated NSCLC and untreated CNS metastases from the KRYSTAL-1 trial (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), in which adagrasib 600 mg was administered orally, twice daily. Study outcomes included the safety and clinical activity (intracranial [IC] and systemic) by blinded independent central review. Twenty-five patients with KRASG12C-mutated NSCLC and untreated CNS metastases were enrolled and evaluated (median follow-up, 13.7 months); 19 patients were radiographically evaluable for IC activity. Safety was consistent with previous reports of adagrasib, with grade 3 treatment-related adverse events (TRAEs) in 10 patients (40%) and one grade 4 (4%) and no grade 5 TRAEs. The most common CNS-specific TRAEs included dysgeusia (24%) and dizziness (20%). Adagrasib demonstrated an IC objective response rate of 42%, disease control rate of 90%, progression-free survival of 5.4 months, and median overall survival of 11.4 months. Adagrasib is the first KRASG12C inhibitor to prospectively demonstrate IC activity in patients with KRASG12C-mutated NSCLC and untreated CNS metastases, supporting further investigation in this population.
Effect of smoking, hypertension and lifestyle factors on kidney cancer — perspectives for prevention and screening programmes
Authors: Riccardo Campi, Giacomo Rebez, Tobias Klatte, Eduard Roussel, Idir Ouizad, Alexander Ingels, Nicola Pavan, Onder Kara, Selcuk Erdem, Riccardo Bertolo, Umberto Capitanio, Maria Carmen Mir
Journal: Nature Reviews Urology (2023)
Consideration of the importance of measuring thermal discomfort in biomedical research
Authors: Cameron R. MacDonald, Jee Eun Choi, Chi-Chen Hong, Elizabeth A. Repasky
Journal: Trends in Molecular Medicine (2023)

Core temperature stability is the result of a dynamically regulated balance of heat loss and gain, which is not reflected by a simple thermometer reading. One way in which these changes manifest is in perceived thermal comfort, 'feeling too cold' or 'feeling too hot', which can activate stress pathways. Unfortunately, there is surprisingly little preclinical research that tracks changes in perceived thermal comfort in response to either disease progression or various treatments. Without measuring this endpoint, there may be missed opportunities to evaluate disease and therapy outcomes in murine models of human disease. Here, we discuss the possibility that changes in thermal comfort in mice could be a useful and physiologically relevant measure of energy trade-offs required under various physiological or pathological conditions.
<i>Tripterygium wilfordii</i>derivative celastrol, a YAP inhibitor, has antifibrotic effects in systemic sclerosis
Authors: Pratyusha Chitturi, Shiwen Xu, Bahja Ahmed Abdi, John Nguyen, David E Carter, Sartak Sinha, Rohit Arora, Jeff Biernaskie, Richard J. Stratton, Andrew Leask
Journal: Annals of the Rheumatic Diseases (2023)

Objectives Systemic sclerosis (SSc) is characterised by extensive tissue fibrosis maintained by mechanotranductive/proadhesive signalling. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol is a YAP1 inhibitor; however, if celastrol can alleviate SSc fibrosis is unknown. Moreover, the cell niches required for skin fibrosis are unknown. Methods Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor β1 (TGFβ1), with or without celastrol. Mice were subjected to the bleomycin-induced model of skin SSc, in the presence or absence of celastrol. Fibrosis was assessed using RNA Sequencing, real-time PCR, spatial transcriptomic analyses, Western blot, ELISA and histological analyses. Results In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including that of cellular communication network factor 2, collagen I and TGFβ1. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of skin SSc, increased expression of genes associated with reticular fibroblast and hippo/YAP clusters was observed; conversely, celastrol inhibited these bleomycin-induced changes and blocked nuclear localisation of YAP. Conclusions Our data clarify niches within the skin activated in fibrosis and suggest that compounds, such as celastrol, that antagonise the YAP pathway may be potential treatments for SSc skin fibrosis.
Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease (ACeD): a phase 1 trial
Authors: Joseph A Murray, Dina Wassaf, Karen Dunn, Samir Arora, Peter Winkle, Helen Stacey, Simon Cooper, Kaela E Goldstein, Rajesh Manchanda, Stephan Kontos, Kristie M Grebe
Journal: The Lancet. Gastroenterology & hepatology (2023)
Fragmentomic analysis of circulating tumor DNA-targeted cancer panels
Authors: K.T. Helzer, M.N. Sharifi, J.M. Sperger, Y. Shi, M. Annala, M.L. Bootsma, S.R. Reese, A. Taylor, K.R. Kaufmann, H.K. Krause, J.L. Schehr, N. Sethakorn, D. Kosoff, C. Kyriakopoulos, M.E. Burkard, N.R. Rydzewski, M. Yu, P.M. Harari, M. Bassetti, G. Blitzer, J. Floberg, M. Sjöström, D.A. Quigley, S.M. Dehm, A.J. Armstrong, H. Beltran, R.R. McKay, F.Y. Feng, R. O’Regan, K.B. Wisinski, H. Emamekhoo, A.W. Wyatt, J.M. Lang, S.G. Zhao
Journal: Annals of Oncology (2023)
First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2–Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non–Small-Cell Lung Cancer: TROPION-PanTumor01
Authors: Toshio Shimizu, Jacob Sands, Kiyotaka Yoh, Alexander Spira, Edward B. Garon, Satoru Kitazono, Melissa L. Johnson, Funda Meric-Bernstam, Anthony W. Tolcher, Noboru Yamamoto, Jon Greenberg, Yui Kawasaki, Hong Zebger-Gong, Fumiaki Kobayashi, Penny Phillips, Aaron E. Lisberg, Rebecca S. Heist
Journal: Journal of Clinical Oncology (2023)

This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC).
Cause-specific mortality in COPD subpopulations: a cohort study of 339 647 people in England
Authors: Hannah Whittaker, Kieran J Rothnie, Jennifer K Quint
Journal: Thorax (2023)

Background Identifying correlates of cause-specific mortality in patients with chronic obstructive pulmonary disease (COPD) may aid the targeting of therapies to reduce mortality. We determined factors associated with causes of death in a primary care COPD population. Methods Clinical Practice Research Datalink Aurum was linked to Hospital Episode Statistics and death certificate data. People with COPD alive between 1 January 2010 and 1 January 2020 were included. Patient characteristics were defined before the start of follow-up: (a) frequency and severity of exacerbations; (b) emphysema or chronic bronchitis; (c) Global Obstructive Lung Disease (GOLD) groups A–D; and (d) airflow limitation. We used Cox Proportional Hazards regression and competing risks to investigate the association between patient characteristics and risk of all-cause, COPD and cardiovascular (CV) mortality. Results 339 647 people with COPD were included of which 97 882 died during follow-up (25.7% COPD related and 23.3% CV related). Airflow limitation, GOLD group, exacerbation frequency and severity, and COPD phenotype were associated with all-cause mortality. Exacerbations, both increased frequency and severity, were associated with COPD-related mortality (≥2 exacerbations vs none adjusted HR: 1.64, 1.57–1.71; 1 severe vs none adjusted HR: 2.17, 2.04–2.31, respectively). Patients in GOLD groups B–D had a higher risk of COPD and CV mortality compared with GOLD group A (GOLD group D vs group A, adjusted HR for COPD mortality: 4.57, 4.23–4.93 and adjusted HR for CV mortality: 1.53, 1.41–1.65). Increasing airflow limitation was also associated with both COPD and CV mortality (GOLD 4 vs 1, adjusted HR: 12.63, 11.82–13.51 and adjusted HR: 1.75, 1.60–1.91, respectively). Conclusion Poorer airflow limitation, worse functional status and exacerbations had substantial associations with risk of all-cause mortality. Differing results for CV and COPD-related mortality suggests interventions to prevent mortality may need to target particular characteristics or time points in the disease course.
Budget impact analysis and treatment availability with biosimilar TNF inhibitors in rheumatic diseases in Poland: real-world evidence using a nationwide database
Authors: Marcin Stajszczyk, Izabela Obarska, Slawomir Jeka, Bogdan Batko
Journal: Annals of the Rheumatic Diseases (2023)

Objectives Although several years have passed since biologic disease modifying antirheumatic drugs were introduced to the market, considerable disparities in access still remain. Tumour necrosis factor inhibitors (TNFi) have proven to be highly effective and safe for treating patients with rheumatic musculoskeletal diseases (RMDs). The emergence of biosimilars is promising for cost reduction and more equitable, widespread access. Methods A retrospective budget impact analysis based on final drug prices was conducted using 12 687 treatment courses for infliximab, etanercept and adalimumab. Estimated and real-life savings for public payer were calculated from an 8-year perspective of TNFi use. Data on the treatment cost and on the evolution in the number of patients treated was provided. Results From a public payer perspective, the estimated total savings amount to over €243 million for TNFi, with over €166 million attributed to treatment cost reduction in RMDs. Real-life savings were calculated as €133 million and €107 million, respectively. The rheumatology sector generated between 68% and 92% of total savings across models, depending on the adopted scenario. The overall decrease in mean annual cost of treatment ranged between 75% and 89% in the study frame. If all budget savings were spent on reimbursement of additional TNFi, a hypothetical total of almost 45 000 patients with RMDs could be treated in 2021. Conclusions This is the first nation-level analysis that shows estimated and real-life direct cost-savings for TNFi biosimilars. Transparent criteria for reinvesting savings should be developed on both a local and an international levels.
Effects of COVID-19 vaccination and previous SARS-CoV-2 infection on omicron infection and severe outcomes in children under 12 years of age in the USA: an observational cohort study
Authors: Dan-Yu Lin, Yangjianchen Xu, Yu Gu, Donglin Zeng, Bradford Wheeler, Hayley Young, Zack Moore, Shadia K Sunny
Journal: The Lancet Infectious Diseases (2023)
Activatable Mn2+-Armed nanoagonist augments antitumor immunity in colorectal cancer: A NIR-II Photonic neoadjuvant paradigm
Authors: Qing Liang, Jiayuan Chen, Shuai Hou, Di Li, Ying Zhu, Ruiqi Li, Lian Chen, Jiao Li, Wei Fu, Shiqiong Lei, Biying Zhang, Xin Zheng, Tao Zhang, Hongwei Duan, Wenshan He, Jinghua Ren
Journal: Biomaterials (2023)